ANXA1-derived peptide for targeting PD-L1 degradation inhibits tumor immune evasion in multiple cancers

J Immunother Cancer. 2023 Mar;11(3):e006345. doi: 10.1136/jitc-2022-006345.


Background: Immune checkpoint inhibitors (ICIs) therapy targeting programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) shows promising clinical benefits. However, the relatively low response rate highlights the need to develop an alternative strategy to target PD-1/PD-L1 immune checkpoint. Our study focuses on the role and mechanism of annexin A1 (ANXA1)-derived peptide A11 degrading PD-L1 and the effect of A11 on tumor immune evasion in multiple cancers.

Methods: Binding of A11 to PD-L1 was identified by biotin pull-down coupled with mass spectrometry analysis. USP7 as PD-L1's deubiquitinase was found by screening a human deubiquitinase cDNA library. The role and mechanism of A11 competing with USP7 to degrade PD-L1 were analyzed. The capability to enhance the T cell-mediated tumor cell killing activity and antitumor effect of A11 via suppressing tumor immune evasion were investigated. The synergistic antitumor effect of A11 and PD-L1 mAb (monoclonal antibody) via suppressing tumor immune evasion were also studied in mice. The expression and clinical significance of USP7 and PD-L1 in cancer tissues were evaluated by immunohistochemistry.

Results: A11 decreases PD-L1 protein stability and levels by ubiquitin proteasome pathway in breast cancer, lung cancer and melanoma cells. Mechanistically, A11 competes with PD-L1's deubiquitinase USP7 for binding PD-L1, and then degrades PD-L1 by inhibiting USP7-mediated PD-L1 deubiquitination. Functionally, A11 promotes T cell ability of killing cancer cells in vitro, inhibits tumor immune evasion in mice via increasing the population and activation of CD8+ T cells in tumor microenvironment, and A11 and PD-1 mAb possess synergistic antitumor effect in mice. Moreover, expression levels of both USP7 and PD-L1 are significantly higher in breast cancer, non-small cell lung cancer and skin melanoma tissues than those in their corresponding normal tissues and are positively correlated in cancer tissues, and both proteins for predicting efficacy of PD-1 mAb immunotherapy and patient prognosis are superior to individual protein.

Conclusion: Our results reveal that A11 competes with USP7 to bind and degrade PD-L1 in cancer cells, A11 exhibits obvious antitumor effects and synergistic antitumor activity with PD-1 mAb via inhibiting tumor immune evasion and A11 can serve as an alternative strategy for ICIs therapy in multiple cancers.

Keywords: B7-H1 antigen; breast neoplasms; immune evation; immunotherapy; lung neoplasms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A1* / metabolism
  • Antibodies, Monoclonal / therapeutic use
  • B7-H1 Antigen
  • Breast Neoplasms* / drug therapy
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Female
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / metabolism
  • Melanoma* / drug therapy
  • Mice
  • Peptides / metabolism
  • Programmed Cell Death 1 Receptor
  • Tumor Escape
  • Tumor Microenvironment
  • Ubiquitin-Specific Peptidase 7 / metabolism


  • Annexin A1
  • B7-H1 Antigen
  • Programmed Cell Death 1 Receptor
  • Ubiquitin-Specific Peptidase 7
  • Antibodies, Monoclonal
  • Peptides
  • USP7 protein, human